Hi everyone, it's Guy Spear here and for

the first time I'm not interviewing

somebody or being interviewed about

somebody about investing. I'm

interviewing two doctors. The two

doctors are in the University Clinic of

Münster where they spend

uh well, they live there and work there,

but I spent a month in hospital uh doing

a special treatment and uh my

introduction is just that I am blown

away by the minute you step out of

investing how

uh there are extraordinary people doing

extraordinary things that you wouldn't

know about if you didn't step into a

different universe, the universe of

medicine and so I just want to show

shine a spotlight on them and we have a

little agenda here and so enough of me

and I guess that what we agreed to to is

that my journey, but you you maybe maybe

uh Professor Mütter and just to be

clear, I was uh the patient of these two

fine doctors and researchers for a month

but we're no I'm no longer their

patient. I just did a study. So I'm

going to get uh Dr. Mütter to go first

and I guess uh you can introduce

yourself and then you will uh I don't

know, you'll talk about what you do

maybe you'll talk about me from a

slightly medical perspective, not too

much because this is for a general

audience. Go ahead, Dr. Mütter.

All right. Thank you very much for

giving us this chance to to speak here

about all these things that are on the

agenda. So my name is Michael Mütter.

I'm a neurosurgeon attending

neurosurgeon here at the University

Medical Center. Um neurosurgery is a

surgical specialty, you know, dealing

with all sorts of um diseases and

problems around the skull, the brain,

the spine and the nerves around the body

and I'm myself I'm specializing on brain

tumors um and the surgical part of brain

tumors and studies around that we're

doing.

Um I uh was trained and I'm I am still

working under the supervision of

Professor Walter Stummer who's my mentor

and he invented some things and

introduced them into the field. He kind

of pioneered some um some aspects of

neurosurgery um that I'm trying to

continue now in my work. Um so

academically as well as clinically I'm

dealing with brain tumors and that's how

we met.

Dr. Mütter or maybe I should call you I

I don't know if it's okay to go to first

names. Sure, yeah. We're we're we're

half in Switzerland we're half in

Germany, you know, but um

uh

do you regret not peering into my brain?

Do you think it would have been a good

brain to look at or they're all the

same? No, they're not all the same.

Everyone's a little different. So um

yeah, I would have loved to do that as

well, but someone else did that, but um

we got together as we have a certain

portfolio on on brain tumor trials

running that we're running here in

Münster and that's how we got into

touch.

So uh Dr. Pepper who I know better

really because I saw you like on a

regular basis except when you were were

in another clinic and I'm blown away cuz

these people are half my age and and

they're anyway. So to go ahead, why

don't you introduce yourself, Dr.

Pepper?

And I don't know, I'm on last names.

What can I say?

Uh yes, thank you very much. I very much

appreciate the chance to talk here about

the the treatment of

um yeah, brain tumors from a radiation

oncologist's perspective as well. Um so

I'm a radiation oncologist at the

University Hospital of Münster for

uh 7 years now and um

my story basically is that I've

uh originally worked with uh patients

with Hodgkin's lymphoma primarily and

wrote my thesis about that, but um

during my work here in the the clinic uh

under the supervision of Professor Eich

which is the head of our department

uh I um

more and more developed an interest into

the treatment of uh cerebral tumors and

um this is how I yeah, came into

uh contact with more and more patients

with uh glioblastoma which is the most

common um malignant brain tumor in

adults and uh it was in

uh 2023

when uh 2022 turning 2023 when uh

Professor Stummer the head of the

Department of Neurosurgery uh approached

Professor Eich regarding the

uh the initiation of a trial

and uh yeah, Professor Eich uh asked for

someone to to be a part of this trial uh

from a from a doctor's uh perspective

and I volunteered and this is how I came

into the trial and since then I've been

very much working on all different kinds

of uh pers- aspects of the treatment of

uh glioblastoma from a radiation

oncologist's point of view which has

been uh developing over the last 20

years quite a bit and it's a very very

interesting field to be working in.

So uh thank you uh Dr. Pepper or

Nicholas. So um if I go back to you uh

and I'm just going to

go with last names. What can I say? It's

just I don't know. I'm in I'm German

enough to want to do that, but you can

always call me Guy. But um

So uh

so the reason why I came in contact with

them is that unfortunately for me uh the

first line of um uh treatment which is

called the Stupp protocol did not work

or did not work very well.

I had uh two recurrences and the uh my

doctor or one of my doctors at the time

uh who knew the German landscape very

very well said this is a good trial for

you to be on. Uh and it may help, but uh

Dr. Mütter, why don't you first explain

what Gleolan or um

5-ALA dye is and how you use it in

surgery?

Yeah, sure. So um the problem with brain

tumors is that sometimes they are they

very much look alike the brain itself or

the diseased brain and there are certain

tools that we use as surgeons to

visualize the tumor. It is with our own

eyes through the surgical microscope or

the uh haptic feedback we get with our

instruments, but sometimes it's uh it's

it's very difficult and then um

additional tools come into play and one

of those is

fluorescence-guided surgery with uh

5-ALA.

Um it's called 5-aminolevulinic

acid. It is uh something that is not

artificial. It's um

one or two may know it from biology

class. It's a degradation

metabolite of um of the red blood cells

in fact. So it's it's it's not something

artificial, but you can you can

administer it. You can you can drink it

as a solution and then it accumulates

all around the body and with the brain

tumor cells it it it doesn't it doesn't

get pushed out of the brain tumor cells.

So it accumulates inside uh the tumor

cells as well as several other cell

types that are necessary for tumor

growth.

Um and so and then you can use light of

certain wavelength which you can you can

just put a filter in your surgical

microscope and then um you you have the

tumor illuminated. So it gives you it

gives you a contrast. It shines in in in

in this example it shines sort of a

yeah, a lava lava

uh

violet um pink. It gives different

shades of of of color

uh depending on the cell density of the

tumor and so you can you can easily

visualize it and make sure that you can

resect

uh the part of the tumor that you want

to resect and that is um that part that

takes up the MRI contrast. We know you

know, from your scans you're you're

getting scans regularly and um tumors

like glioblastoma they they light up in

this contrast and that's that's the

stuff that we want to take out um and

this Gleolan this fluorescence-guided

surgery or resection helps us very much

with with doing so and even going

beyond.

Yeah, uh just briefly uh that's not the

only thing. I mean, you have to take

care that you don't cut out parts of my

brain or somebody's brain that actually

you may need after your surgery. Yeah,

absolutely.

>> Yeah. So you may have situations where

you are

you the 5-ALA dye lights up

but you have to be sensitive to other

other

factors which don't allow you to take it

out or you have to be very careful. And

I know that you have

with in the surgery you have somebody

who's just responsible for checking uh

what is it called? Um

uh uh potentials of different parts of

the brain to make sure that they're not

be being used for somebody something

else. Can you just go into that for a

second? Sure. So the problem is like

with many other organs inside the human

body that most of it is of function um

and that's particularly true for

particularly true in the brain as as

most of the brain is of is of is is

functioning. Is it for for motor

responses or for vision or uh for speech

and we have different modes of taking

care that

uh this doesn't get injured or we get

pre-alerted during surgery that we are

uh approximating uh a certain very

sensible part of the brain. And this is

uh this is why for

for almost every surgery we have an

electrophysiologist with us um and we

can do certain tests while you're uh

under uh general anesthesia and we for

for certain

functions that we want to test such as

for speech, we need the patient's

feedback. So, we have certain patients

that are awake during surgery. It's a

It's a very established protocol to

operate on patients being awake for

especially for for for checking for

speech problems

and language as well.

And that's that's been done all around

the all around the world nowadays.

And the patient only have a

local anesthesia of the skull and

the meninges or the

the skin on the brain. That's That's the

the brain itself doesn't feel any pain.

So, with that you can check with a with

certain

electrodes, you can sort of numb the

brain for a very little time and then

give the patient a task to accomplish

such as reading or pointing at numbers

or calculating or something and if we

see the patients are

stumbling, then we know that part of the

brain is important and we have to leave

it there. And that is something that we

develop over time during surgery and

then we have to find a so-called

onco-functional balance. So, we have to

find balance out the function and the

oncological benefit that the patient has

from resection and that is a fine line

sometimes and takes

takes a little experience as well.

So, we can't just take away everything

that lights up with a with a

fluorescence. So, we at the same time we

have to think about the function and

what it means if we did take this out.

So, that's basically what we do in brain

tumor surgery. So,

in case you're interested, I am

I could never if you know that if I was

in your field, I'd be in the direction

of Dr. Pepper. I could not do how you do

it. I have no idea how. And just for

your interest, those who are listening,

I was not woken up during surgery for

whatever reason and

we we we we could not do a biology

course or a neuro

neuroanatomy course in a in an hour and

a half or what we have together. But I I

don't even want to and I don't

I don't even want to get into the

discussions that you have before and

after surgery. I just can't imagine, but

I'm grateful that in the three surgeries

that I had so far, I was not woken up.

So, um

but the next thing that happened to me

after my first surgery is that I got

radiotherapy.

So, I so so

Dr. Pepper can explain it a lot better

than I can. Why don't you explain what

I've been through and why I was

re-radiated?

Yes. So,

I think that's a good point. I would

just take step backwards because a lot

of listeners might not be familiar with

the concept of radiotherapy and

radiation oncology as a as a whole.

The main part is that radiotherapy today

is a is a very important cornerstone of

oncological treatment in a lot of

different circumstances and it this

basically goes for all kinds of

different tumors. So, we're not just

talking about brain tumors, we're also

talking about tumors of the lung, tumors

of the the breast, the prostate, all the

familiar tumors

are

irradiated in some kind or another or

for in different scenarios.

And

the reason for that is that

like Dr. Pepper just previously

explained, the surgery alone is

not enough so to speak because you can

only take out a certain part of

the brain and we've learned in the last

couple of years that especially

glioblastoma is a disease that

uh

tries to infiltrate the working part of

the brain like a network in a way and

so radiotherapy has been very

established for a long time in the

treatment of

brain tumors because we

most certainly know that for most types

of brain tumors after surgery itself,

there are still some cells left around

the perimeter of the main tumor who can

then

grow and can cause a relapse of the um

of the tumor. And with radiotherapy, we

try to target those cells and try to

eliminate those cells. And what we're

using for that is ionizing radiation

mostly in the form of photons and

depending on the

on the tumor itself

and location of the tumor, electrons as

well sometimes and photo protons also

used in

the radiation of tumors, brain tumors,

but also different tumors.

And those are

types of radiation we're using as a

local treatment to kill those tumor

cells. And for the first line treatment

of glioblastoma um

we use a a 6-week course of radiotherapy

um which has been agreed upon uh

based on study data and in this study

data, the 6-week dose of what is

cumulative 60 gray, which is the

the

number so to speak for the

uh radiation dose

uh has been applied because

for

yeah, mostly all the

yeah, the most types of radiotherapy,

we're doing what we are calling a

fractionated radiotherapy because if you

would apply all the dose all the doses

of

for the radiation at once, it would be

detrimental for the

uh healthy tissue as well. And for us

like for the surgeons, we have to find a

balance between killing the tumor cells,

but also

uh not harming the normal tissue and the

remaining tissue as much as possible.

And uh with this type of fractionated

radiotherapy, [snorts]

we can find a balance between treating

the tumor to a degree where it has been

ultimately killed and also not harming

the normal tissue. So, which is this is

why radiotherapy is not done in one

session like most surgeries are, but

normally takes up a lot of time and like

you just said, a 6-week course of

radiotherapy is the

uh

the common treatment for glioblastoma in

the first line. And just for what it's

worth, um

uh you know, and again, this is very

surface level knowledge, but they have

they have ways of focusing the

um the uh

uh x-rays if you like or the the

radiotherapy in such a way that only the

tissue that you need to get irradiated

gets irradiated and it's it's pretty

cool system and they're very expensive

machines that you go for, but literally,

I was there for a month. Uh but really

the treatment was 5 days a week um for

10 minutes.

And then I had then I was resting

effectively the rest of the day. And I

guess um that's true of many other kinds

of radiotherapy, not just mine, I guess.

Yes. Uh that's that's the

most common type of radiotherapy. So,

it's

very few very short hours a very very

short treatment for every day

uh of a long period so to speak. And

I completely agree what you just said.

So, the

we are able today to focus the x-rays on

a certain area which we call the

planning target volume. So, it's a it's

the target volume which identified as

the

uh area that's been in risk to hold

tumor cells plus a certain uh margin

around this area

just for safety measures

as well. And this area is then

irradiated with a dose which has been

prescribed at the beginning of

treatment. And regarding the dose for a

second course of radiotherapy

we know that we are limited because we

can't apply the same dose

like we did in the first time.

And this is because for the

uh so, once again, if I if I take a step

back, for for the longest time actually,

people believed that one course of

radiotherapy was all that was possible

and that a second course of radiotherapy

was basically impossible and

would be too much and too toxic for the

for the brain

um because

um of

yeah,

uh prior trials which have shown that if

you go over a certain dose, then the

risk for

uh side effects and for necrosis, so

the dying of healthy tissue is too too

big. But we've learned a lot in that

regard and I think it's safe to say that

today

the second course of radiotherapy has

been very close to a standard in the

treatment of brain tumors.

Uh and this has basically changed just

about 20 years ago

when the first reports regarding the

first appearances of re-radiation of

brain tumors uh were published.

Interestingly, this is this is kind of

around the same time when

Professor Stummer first published about

the

uh

yeah, the effects of Gliolan in in a in

one of the most famous uh and

prestigious medical papers where he

wrote a very very big article that uh

basically put the Gliolan on the map

worldwide and has been able to establish

that as a

local treatment as a treatment in

neurosurgery. At the same time, the

first reports regarding re-irradiation

were also published from from colleagues

here in Germany.

For example, uh two

two very very famous colleagues in this

regard are

uh this is Professor Combs and Professor

Grosu who are very who are now today the

heads of the departments of radiation

oncology in Munich and in Freiburg and

have been working with the

um neuro-oncology working group, so the

brain tumor specific working group of

the

German

um Cancer Association at the time and

has been pioneered have done pioneering

work in that in that matter and build on

that experience at uh publi- published

larger amounts of patients and were able

to show that second course of

radiotherapy is doable. It's it has a

low risk for toxicity, has a good safety

profile, and it's also

uh more effective than what has been the

standard before that which was just

um

just chemotherapy. Uh so, yeah, the

re-irradiation has been

established, so to speak, in the

treatment of brain tumors in in that

way.

So, you know, I I get to to to say

something that um just for fun before I

go to my next question, which I'm really

looking forward to asking, is that um

you know, first of all, thank you for

doing this in English. It's not your

mother tongue, you know, and maybe you

know, as we all know here and you may be

aware, the audience um this well, first

of all, they're in

Münster, which is by the way

as beautiful as Oxford. It's really a

lovely place to study and there's it's a

university town. There are many students

there, but um there are multiple statues

of Professor Röntgen, who was a German

guy who discovered uh the X-rays I don't

know how 100 years ago, something like

that. And I think to this day

there is a lot of great and I don't

really know because I'm not

uh in the field, but there's a lot of

great science that is done in Germany

that for one reason or another is not

spread quickly or or fast enough around

the world and I think to the extent that

I can help do that by this podcast, if

that happens, then I'll be grateful. But

now I get to ask uh

Professor Pepper a question that So,

when when they're in the hospital, I

don't know if some of you will have been

in a hospital and people like the minute

you have a white coat on, especially if

you're

uh a senior doctor, you have calls on

your time constantly. I can't believe

that neither of your phones has

has rung actually. But um

and even as the patient, even as a

valuable patient, you know that they

have so many other calls on your time.

So, I know that you've done this once

before, but it seems like it's first of

all, it's very beautiful. It's it's a

very it's a very elegant idea that the

very thing that you do that that you

explained how the um

the normal cells metabolize the ALA dye,

the uh the cancer cells don't, and then

there's a mechanism by which they're

weakened uh and make them more

vulnerable to radiotherapy. And you I

know you could spend 2 hours on that or

3 hours and probably you do when you do

lectures. And by the way, there's a

whole school of medical students, which

is right next to the hospital. I was

offered to go in. I didn't go in. Maybe

next time when I come back, I'll go in

and take a look. But um now I get to ask

the question and he's like sort of

committed to my time for a while. So,

how does that work and why did why did

it take so long for somebody to actually

do a study on it? If you knew about ALA

dye

uh 20 years ago, it seems like it's an

obvious idea to to do what you're doing

now with my the study that I'm on. Blast

away.

Um Yes. Good luck. Thank you. So, uh so,

yeah, I mean, uh it it kind of depends.

First of all, I I want to say I turned

my phone off. That's why I didn't bring

my phone.

>> [laughter]

>> Because because otherwise they

these guys are so much in demand, you

can't believe. Anyway, yeah.

Yeah, so uh the

um the the reason why this kind of took

a while is because

like like I um

talked about before, the

uh re-irradiation as itself, we we had

to come custom to that at first

before we were able to do

uh further steps and then

uh try to enhance the treatment. And

enhancing the treatment is basically the

idea which we

uh which we were focusing on because

um like I just said, the the normal

tissue um has to be cared for when

you're doing radiotherapy as a whole and

especially when you're doing

uh re-irradiation because the normal

tissue doesn't forget the prior

irradiation.

And so, what would be the thing that you

wish for as a as a radiation oncologist

would be some kind of medicine or

something that you can give the patient

that lets you achieve more with less

radiation dose. So, uh that's what we

call a radiosensitizer. So, something

that works preferably just in the tumor

cells

and somehow doesn't affect the normal

tissue. And um with the 5-ALA, I just uh

just

uh touched on that a little bit that um

Professor Stummer already 20 years ago

published uh groundbreaking articles

about that and uh at the same time

uh first reports on re-irradiation

surfaced and then 5 years later

uh bigger reports regarding the

re-irradiation. But for the next step to

happen, it uh actually kind of took a

took a while because

um the connection between the

uh 5-ALA and the radiotherapy, that

uh took a while. And before you can

transfer the findings which were then uh

made um especially by uh several working

groups in Japan who's been working in

this field as well for a for a long

time, that you can also use radiotherapy

to kill tumor cells that have been um

loaded with 5-ALA or the the different

parts of ALA that

uh actually mediate the

the effect of the 5-ALA.

Um this has been this took quite a while

and so, we actually started developing

this trial

uh in Münster 6 years ago and Dr. Müller

is actually working um

in the fields uh with the 5-ALA, which

doesn't only use the radio doesn't only

use radiotherapy, but also what we call

photodynamic therapy. So,

um the stimulation of tumor cells who

are holding 5-ALA with uh light of a

certain wavelength,

which doesn't only show the tumor, but

also kills it with a laser, so to speak.

And the

um idea is for the photodynamic therapy,

you have to get the laser parts, the

diodes, the uh light directly into the

tumor, while with radiotherapy, you can

do it externally and you can just

uh use the linear accelerators and the

X-rays can penetrate the brain and uh go

into the tumors and have the effect

there without having uh to do a surgery

and do a

uh put the patient under anesthesia.

Uh but yeah, to put all those pieces

together, it really took

quite some time. And we're the first

ones who are doing a a trial uh with uh

humans uh in that regard. So, there's

been like I like I said before, a lot of

uh other broad shoulders which we can

put our research um uh on.

Uh for example, the colleagues in Japan

who's been uh doing all those wonderful

uh cell trials and animal trials, and

have shown that the effect is there and

that it's um also doable with

photo-irradiation.

And uh based on that, we were able to

um produce the trial and then later on

open the trial. But

before we can really start with the

first patient, you have to go through a

lot of

A lot of There's a lot of rules to

follow. Yeah. You have a lot of rules

which you have to follow and uh a lot of

checks you have to be made on uh certain

checklists before you can start with a

trial. And uh of course, when you're

doing a trial with a uh with something

that's a combination of treatments that

are done for the first time with human

patients,

uh the safety regards are very very

high, which is uh rightfully so.

And uh the regulations are very very

heavy, and we have to uh get all the uh

prior security checks first, and that's

why it took a long time.

Why

uh

this this is where I get to like So, at

this point if if um if

uh

Dr. Pepper is doing his rounds, he's had

three phone calls and three people have

tapped his shoulders, and he's in a

different thousand different directions

that he has to be in. But,

why do we know that the um

the So, so we know that it it stays in

the in the cancer cells, and it gets

metabolized in the non-cancer cells, but

why do we know that it makes any

difference to the

like you you would want to say that

um

the 5-ALA dye absorbs more of the energy

of the um of the x-rays that are coming

in, but uh that depends on maybe the

frequency of the radiation and a whole

bunch of other things. Uh why do you

What is the theoretical basis for why

that is actually has an effect? I mean,

maybe maybe it's like glass. It's just

the the 5-ALA dye is just transparent to

the uh to the radio waves, you know?

Yeah. So, um

like uh like our co-worker previously uh

said, the

5-ALA gets metabolized in a different

way in the tumor cell, and uh we have a

a product of the 5-ALA metabolism, which

is called uh PP9, protoporphyrin IX, and

this

uh

accumulates in the tumor cells. And so,

while the the whole story of the

mechanism is still topic of further

research, we know so far that uh the

most of the effect of the what we call

radio-dynamic therapy, so the

combination of 5-ALA

uh with the radiotherapy

uh is mediated by the protoporphyrin IX,

which is met by the ionizing radiation

and causes reactive oxygen species. So,

a lot of our cells or most of our cells

have oxygen loaded into them, and um

this oxygen can

be

used as a as a mediator of cell killing,

uh which is something that also happens

with normal radiotherapy,

but especially happens for cells which

have uh the 5-ALA inside of them. And

the reactive oxygen species then

just tr- yeah, basically attack

different parts of the cell of the uh

vital organs of the cell as well, and

this causes the cell to die.

So, that's the theory.

Do you ever get sick of tr- trying to

explain that? But, I mean, I imagine

that every single person on this study,

for example, wants to have some version

of that explained to them. Do you ever

get sick of explaining to it it? Because

at the same time, there's a limited You

are

in yourself trying to advance the

knowledge. There's a certain amount that

you know, and then you have to break it

down to sort of like simple things for

people like me and the all the other

trial patients to uh to explain. Is it

Do you get not get not get sick of it,

but do but it's like

you're not You know what I mean? You're

kind of explaining to dumb people in a

way. I mean, on the one on the one hand,

we're patients, and we deserve to know.

On the other hand, you'll never be able

to actually explain what's really going

on, because it's difficult, you know?

>> Yeah. Yeah, that's that's that's the

interesting part,

because

uh to be honest, it's it's it's very

hard to explain something [snorts]

that hasn't been understood fully as a

whole. Because um

there's still so much work to be done

about the the effect for clinical

trials.

You have to have the

uh

ground research. You have to have the um

the the the models which show the

effect, but sometimes the effect and how

it actually works

uh it's not

100% understood. And uh for the at least

for me, for 5-ALA and the work process,

it's it's the same in a way, because we

have a lot of information

uh why it works and how it works, but uh

there's So, the the human body and every

human cell is such a complex

concept and such a complex specimen that

the the whole story of what happens, and

for example, why the 5-ALA is uh

metabolized in the way it is metabolized

in glioma cells uh differently, there's

still much to be learned about.

Yeah.

It's uh you know, um

I think that one thing that I've

learned, and you know, about biology in

general, is that um there are many

networks. We we know about complex I

know about complex adaptive systems, but

in in in um biology, the complex

adaptivity happens on multiple different

scales. So, you have the molecules that

are very small scale, you have chemicals

interaction outside the cell, you have

kind of like different scales of

operation, and you can be specialized in

only one certain part of this, which is

why, for example, maybe this is a a nice

segue.

Uh you you know, I see a doctor, I see

two doctors, and you know, your your

knowledge interfaces a little bit, but

then you have all these other ways. I

mean, I'm trying to understand now a

little bit betw-

what kind of T cells there are, because

And then there I've learned there's

something called a a dendritic cell. And

uh there are all these other therapies

that come in to play. And so, why do we

start here? Um

So, you your your study, and maybe you

can do just 5 minutes or less on what a

dose escalation trial is and why you do

it, and why the end points are basically

just safety, and you didn't go to the

next step of looking at uh survivability

or some other kind of uh something that

I would prefer to that you you looked at

actually, which is does it work, you

know? The usual sequence is is

traditionally in science, and that's

scientific etiquette, if you if you

want, um is that you come up with an

idea, then you go into the petri dish,

so in the lab, that's a wet lab

experiment, then you go into animals.

And if that all works out, because as

you said, the complexity is on a

multiple levels um other than maybe in

economy, and there plus there's the

unknown, as you said. And then that's

the reason why you have to go so many

steps until you can finally go into an

early clinical phase study, that's what

this was.

Um and then you first you focus on is

this treatment really Is it safe? Is it

safe to go on and treat more patients?

And that's the reason why these early uh

trials, and we we we understand

different um different phases. We This

is a phase 1/2, and then we go into two,

and then three. So,

phase one studies are very early, and

they concentrate on the end point of

safety, and that's the primary end

point. That's how we calculate how many

patients we need to answer our question.

Um um and if that was answered

positively, and if if if we get what we

we're wishing for, then we escalate, and

then we change the um the sample size a

little bit. We can treat more patients,

and then we can go on into is is there a

real such as with brain tumors, is there

an oncological benefit? Are survival

times prolonged? Are there Is there a

better quality of life? That's another

end point, which is very important, and

gets even more important. That has been

neglected a little bit in the last

decades, but it's becoming more and more

important, and obviously it is important

how how people feel um with their

disease.

Um yeah, that's that's that's basically

um

what needs to be done on on needs to be

said.

Uh needs to be asked your question.

I think. Yeah, and then dose escalation,

maybe Nicholas, you can go into much

more detail, but usually that's that's

also what we do with other trials that

we are running on our side from the

neurosurgical department. If you titrate

into something into your cohorts,

um you you try to start If you want to

find the dose, you start with a lower

dose, and you treat a certain cohort,

and then you can escalate into the next

cohort,

uh [snorts] treating more patients with

a higher dose. Um that's usually how it

works. And with this um so,

radio-dynamic therapy, we start with a

couple of times of of of the drug being

administered prior to radiation, and

then we escalate into more times. We

don't escalate the dose itself, but it's

the frequency of of application. Yep,

correct. So,

uh for for our trial, we uh chose a uh

basic what we call a 3 + 3

um dose escalation protocol. Uh I'll

get on that in a minute, but uh so, the

idea is we have to have the uh 5-ALA

inside the tumor cells for it to work,

and we have a longer period of uh

radiation treatment. Um like we talked

about before, it's been uh

it's over the course of several weeks,

actually. And um

so, the basic science and the

experiences from neurosurgery just apply

it one time for for a surgery, for

example.

Uh and we are the first uh trial to do

multiple applications of uh 5-ALA in

this

uh context, and uh this is why we

actually started with

um,

one application because of the surgery

and one further application uh,

with the treatment and then build on

that with this uh, dose escalation um,

study just adding for each cohort

uh, one more application. So, the final

um, number of applications will be

eight. Uh, we are hoping to reach that

this year.

And um, how the 3 + 3 dose escalation

uh, module works.

Uh, it's basically all uh, focused on

uh, toxicity of the treatment uh, and

how well like uh, Dr. Mitre just said

how well the patients um,

are doing with the treatment and if

there are any side effects. And we're

putting three patients under the same

dose level in each cohort.

And if they are if none of them have any

side effects, it shows us that it's a

well-tolerated dose and we move on to

the next level. If one patient has a

side effect, which we call a major side

effect, so something that would tell us

to alter the dose

we would then

repeat this cohort. So, with the same

dose level three

uh, other patients would be

treated inside the study. So, we would

then have six patients and if one or

more patients of the dose levels or two

uh, two patients or more of the dose

level

uh, would have side effects, that would

be considered

uh, too toxic and the prior dose would

be the maximum tolerated dose, which is

what we are finding, which is uh, trying

to find in this uh, study. So, the

maximum tolerated dose

is what we're aiming for at the moment.

And for your interest uh, for the for

the for the listeners' interest, I was

on cohort six. So, I had six uh, uh,

doses of ALA dye. So, in my lifetime

I've had eight doses, two two in

operations and six during the treatment

and uh, other than uh, a little bit of

uh, nausea, which was not pleasant, but

it was fine. Uh, so um,

uh, but it what's interesting to me and

we shouldn't dwell on it is that I know

that you know, in a way you know 100%

that you wouldn't start doing the trial

if you had any doubts as to whether it

would be tolerated. You you in a way

have no doubt, but you still have to go

through it. And uh, you know, you you

would probably

you would probably give that you could

you could drink it every day for the

rest of your life and you wouldn't have

that much problems with it because you

because I didn't realize until this

podcast that it's something that it's

that it it's something that is natural

to the body anyway. But um,

and and another question that I wanted

to ask when I did the ALA dye,

I had to I also took um, extra oxygen.

Yeah. And and some people when I was

walking around the hospital, they

thought that I had uh, you know, some

kind of heart disease or lung disease

and I was like, "No, no, no, it's not

for that." And so, for example, I'd I'd

I'd have this kind of like uh, feed for

oxygen. And then they think that I

needed to put it on after the radiation.

I was like, "No, I don't need to put it

on anymore. It's all fine." And do you

want to explain what was that was about?

Yeah, that was uh,

like uh, I previously mentioned shortly

that we are seeing oxygen as a mediator

of the cell killing inside the tumor

cells. So, this is why uh, patients uh,

during the trial also

get oxygen prior to the radiation

treatment. So, just to load up the body

with as much as much oxygen saturation

as possible for

uh, the treatment just to

maybe get even a little bit more extra

effectiveness out of it.

And um, so something I I wanted to uh,

also um, maybe point out a little bit

more is

like you said before, we are not

focusing too much on the survival uh,

part of the of the end points of the

trial, but of course we are looking at

the patients and how they are uh, how

they're doing and if if we see a

potential benefit when we compare it to

to other trials we did in the past and

to

uh, other cohorts we've treated.

And um, for this kind of trial it also I

think it's worth to mention that to do

such a trial

you have to have a a cohort or a group

of patients who are

as close to the same as they can be. So,

you can see the results in a in an

optimal way without having too much uh,

different uh, confounders and uh, some

other aspects that might influence the

treatment. And uh,

at the stage of the trial we're at the

moment now, it would be very hard to

find those patients. And I think the

hope for the for the treatment itself is

that it can later on be um,

combined with all

sorts of other treatments because from

from our perspective uh, the 5-ALA like

you like you said before

uh, has a has little amount of side

effects. And uh, the idea and the hope

is that it can also be combined with uh,

chemotherapy during the radiation

treatment and

um, with other parts or with other kinds

of treatment without having to worry

about um, side effects that are

uh, playing off of each other.

Right. So, uh, as you can see, uh, you

have to decide whether you want to go

into I mean

in a different world I would have joined

you in your research, but I guess I am

joining your research participation. But

um, so you're doctors, but you're also

researchers. Uh, part of your work is to

meet with other scientists to find out

what's going on in the world, to read

papers, to encourage people to join you

in doing the research and not becoming

finance guys like myself. Although you

have to know that at least once or twice

I told Dr. Mitre that if he wants to

become a venture capitalist, I'm sure

he'll do really well. But um, do you

want to talk about just how you interact

with other scientists who are trying to

solve the same problem from a different

direction?

Uh, that part of your work. Part of your

work is just clinical work. But part of

your work is research and networking and

finding new ideas and um, I don't know

if I've given if if it's too broad or

uh,

Dr. Mitre is nodding, so go ahead.

Yeah, yeah. I mean, sure. Especially for

the for the field of brain tumors, you

you you just have to accept that you are

not the only person to treat the patient

or to cure the patient. You need a team

effort. It's just so necessary because

you know,

as I said um, the tumor it

especially the glioblastoma, it it grows

inside the normal brain. So, you can't

just if you want to heal the patient

take the tumor completely out, you have

to and

you have to remove the brain in fact.

And nobody wants that of course. So, I

have to leave something behind. So, as

take as much as as is safe and then

the rest needs to be treated as well.

That need that that that was left behind

that that is done by by Nicholas and and

his colleagues. And then there are other

people that specializing on on on

chemotherapy or or other special

treatments that are under on the

investigation. And and and with that it

is it is so important to talk to other

people and think outside the box and um,

and that is um, that is something that

is done all around the world and also on

a national level. Here in Germany we

have the German Cancer Society and they

have a sub branch for for

neuro-oncology. So, all tumors that are

growing along the nervous system either

central or peripheral nervous system.

And we meet with radiation oncologists,

neurosurgeons, neurologists,

uh, neuropathologists,

uh, neuroradiologists,

trialists and and and other specialties

that we need and also basic science

people uh, that are all necessary to

really

um, present that we can all proceed

together in this field cuz cuz we're

dealing with a lot of very rare

diseases. See, it's not it's not you

know,

a lung cancer or or breast cancer that

is that is um,

it's just you know, all these we have so

many different cancer types in the brain

or that are that are possible.

Um, and that's the reason why we need so

many people and bright minds that stick

their heads together to to really go on

and

uh, maybe you you you you said that

before cuz the first line of treatment

after diagnosis, that's pretty much

clear what needs to be done. That's in

the guidelines. But after that with the

first recurrence all gone, the

guidelines usually say that you have to

go on to a trial. And we need those

trials. We need

we need the science. We need the

clinical research

uh, to proceed and really see what what

treatment really works. And that's the

reason why why research is such a big

uh, part of of treatment of these brain

tumors. Yeah.

But so um,

so when were you last No, you you're

the last you in Ravensburg or that's

about to happen? Yeah, it's about to

happen. That's that's the annual meeting

of the German Society of Neuro-Oncology.

It's going to be in in May in

Regensburg. Yeah. Did you want to talk

about a little bit what are you going to

do there? Yeah, so we have a couple of

trials here on our side that we're going

to

that we're going to report on

as a progress report and then there are

several scientific sessions on all

different kinds of treatment, you know,

um

especially of interest is molecular

molecular therapies, so all the genetics

and the genetic workups and diagnostics

they're getting better and better and we

try and we're we're tending or

especially also in cancer medicine in

general, we we will we find alterations

in the genome of the cancer cells that

some of them can be

can be addressed with very special

medication.

And that's usually quite expensive

medication. It's not the usual chemo

drug. It is it is something called

targeted therapy.

And that is a field that is that is very

much up-to-date and with that we can we

can

um

over decades, you know, there's there's

been so much

so many so many genes that were found,

so many drugs that were developed in in

over the time and that is something that

is definitely of interest right now and

I just

we need to talk about this. We need to

talk about who which patient needs to be

analyzed and which drugs are on the

market, which really, you know, um

finds way into the brain because that's

a problem. Not all drugs are working

inside the brain.

Um

only a very few and that is one of the

one of [clears throat] the

biggest problems in fact in in

neuro-oncology that that we only have a

few drugs that we know that are working.

Um

Why is it

>> that I want to add to

this

>> list of topics there. What we also will

host once again is

something that Dr. Muta himself actually

developed, which is the curriculum of

the German Cancer Society's branch of

for neuro-oncology,

which is especially designed for

younger colleagues and for colleagues

who are getting to know the field of

neuro-oncology and the treatment of

brain tumors and want to

get to know the treatment from all

different angles because

for for example, for me, I'm a radiation

oncologist. I've just been treated as a

radiation or trained as a radiation

oncologist

and learning about all the different

aspects of

radiation oncology for all different

types of tumors, but to really

understand the treatment and to expand

the horizon

it's a very very good idea to also

understand what the other disciplines

and the other doctors treating the

patients are doing as well. So what Dr.

Muta did few years ago, I think four or

five years ago, maybe

Michael Yeah, three years ago. Yeah, he

started a curriculum for

all people who are interested and wanted

to know how the treatment of tumor

patients works from a neurosurgeon's

perspective, from a oncologist's

perspective, from a radiation

oncologist's perspective,

from people who are working

in the

uh

rehab facilities and from a

academic point of view. So all angles of

treatment are addressed and we are at

the moment hosting those curriculums

twice a year for everyone who's

interested in the treatment of cancer of

brain cancer patients. It's a very very

interesting

um

program to be joining.

And you know, just again, part of my

interest in doing this is that um for

some reason I don't you know, maybe you

have explanations, it doesn't really

matter. But um I think that Germany

is uh

the most advanced. I know that when it

comes to diagnostics

and for example, sequencing brain

tumors, and it's not just sequencing the

the DNA itself. There's various

different peptides or peptidomes that

you can sequence, so it's it's not how

the DNA is, it's how the DNA is

expressed in a particular cell or in a

particular body.

Uh why is it actually I will ask the

question. Why is it that uh Germany is

so far ahead? Is it just that Trump has

cut funding to

to medicine in the United States or what

what's going on? I mean, Germany used to

be the best at this. Uh Röntgen was a

German. Um

is it

why is Germany so far ahead?

And for example, I was in I was talking

to a a a colleague a

somebody in my family who's a doctor and

he actually said that the the the best

research is being done in Germany. And I

don't know why, maybe I'm just an

Anglophile or something. You you think

that the best research will be done in

the US universities, but it's not the

case here.

Well, that's a good question.

Not sure if we find the exact answer on

this call here, but I think, you know,

back in the days with Rudolf Virchow and

and Robert Koch, um

everybody had to learn German because it

was the the the language of of science.

I think that was a long time ago and

many people moved to

to North America and the US also for

other reasons obviously, but um

you know,

there's a lot of activity there and

there are so so many more Americans than

Germans, but

for for whatever reason, we we have a we

have a good environment here.

Uh good research

um

support by by the government, many open

and public grants that you can apply for

for your research and there are certain

little nests of of research

especially in southern Germany um that

work very well and that produce a lot of

good results and good research

and the pipeline of, you know, going

from

uh from basic research into

translational research and clinical

trials works very well in Germany for

whatever reason because we know that the

regulatory environment has become very

very strict. It's not only in Germany,

also in Europe, which makes, you know,

conducting a clinical trial a large

endeavor and it it takes so much breath.

Um but we're doing it as in

it for whatever reason it works. I think

there is there may be some historic

reasons for this,

but if you know, if if if one one person

or one one leader one dinosaur starts

his work and many many people are

following. I think this is also much

about mentorship. Um like in many other

fields of human existence.

Um I I guess that this is one of the

biggest drivers.

Yeah, so I I Yeah, go ahead, Nicholas. I

I I totally agree. I think that the

like you said, the mentorship and

especially the the networking aspect of

the and the possibilities we have here

in Germany especially like the

neuro-oncology working group, which has

been blessed with a lot of a lot of very

very passionate people who are doing a

lot of

great research and

so the I think most of the trials that

you just

mentioned that your colleague also

mentioned that are done in Germany

brought to light of day by a lot of

trials are brought to light of day by

the neuro-oncology

working group and

we have a lot of very very passionate

researchers who have a good hub there to

just

just bounce ideas off each other and

work together and also refer

patients who are fitting certain trials

to one another

and the network that has been

woven over Germany in this regard is

very very helpful for that.

And so I have so

I will say this because obviously this

is primarily an English-speaking

audience, so if you're thinking about

whether you want to participate in a

trial in Germany or particularly in

University Clinic in Münster, I can

highly recommend it. Um don't think that

it's just for Germans. They are very

welcoming of people from all over the

world. And so just consider it if you're

thinking about it. But my last question

to you is

before you go back to all your phone

calls and and all the other things that

you have to do is

should I I think that leave out

Ravensburg, but should I attend as an

individual

a patient, if you like the

the neuro-oncology association meeting

in Münster coming up later this year?

Oh, absolutely. I mean, we've always

said it would be a great honor to have

you with us.

And

besides

your person I think the whole field is

changing a little bit. I mean, the

people the Society of Neuro-Oncology of

North America is is already um

is is is already doing this that all the

conferences are open to patients as

well.

And there are certain workshops that

patients can participate and this whole

patient involvement is getting more and

more important. Obviously, it is

important. I mean,

um

if I create a trial that is so

cumbersome that a patient wouldn't

wouldn't last uh

the whole trial,

um it doesn't make any sense cuz cuz I

can't I can't use any of the data. Uh

and that's the reason why involvement of

patients is so important and not only in

our trials, but also in the whole

treatment process. And many of there are

other things that I mean, we can't

change we can try to change

perspectives, but um it's it's always

something different if a patient has

um has his thoughts and and and and

tells us about what he think he or she

thinks um um about a trial or about um a

clinical treatment um or a sequence of

treatments or how they um are they

treated and and and what their wishes

are. I think that is very very important

and I think Münster um our our our

conference, so the German society meets

twice a year. The

the first the the first meeting will be

in Regensburg in May and then in October

we're going to have the second meeting

in Münster.

Um this is going to be the first

uh first conference where we are where

where we will have a proper patient

involvement.

You know, uh so um

just as a complete aside as we kind of

wind down this wonderful conversation. I

really appreciate you spending the time

with me is that I have a friend who's a

math professor and he nearly took a job

I I actually took a photograph because

there's a new math building going up or

a new math and physics building and so

he he might have gone to Münster, but he

came to Zurich University instead. But

um [clears throat]

you know, from my perspective

uh so when I was first diagnosed with

what I have

I didn't want to think about the medical

side. I was afraid of thinking of the

medical side and and there's a there's a

there's a um I think it's from Carl

Jung. I'm not 100% sure. He said the

cave or maybe it's a guy called Joseph

Campbell. The the cave you dare not

enter to contains the treasure you seek.

And you know, I thought I would be just

a guy who's trying to make money in the

hedge fund space and now I realize that

I have to engage with the disease that I

have which actually comes from the

Thomas Mann um

the Magic Mountain as well. He says

somewhere in the book that you have to

engage with your own disease if you

like. And so I'm engaging with my

disease if you like because it it seems

like that's what I have to do in my

life. That's what I'm being required to

do. And so that the start is to to to to

talk to you fine folk and maybe I hope

to come to the conference in Münster and

learn more.

Um I will ask this question though.

You know, in a certain sense all we care

about the patients is just cure me, you

know, and let me live my life. You don't

want to have a disease. And is it really

helpful? I mean, if I if I knew

you know, in a way what we want is just

to to be cured without having think to

think too much about it. I'm not being

given that option, so I will be thinking

about it, but um is it really helpful? I

mean, in surgery you don't want a guy

like me looking at you while you do the

surgery because it's a you know, you you

just want to to be 100% focused on what

you need to do. So

um it's a bit of a woolly question, but

I don't know if you want to try and

answer it.

I think you could answer it with a very

much depends. It's very very

different for every individual.

I think um it can be a good strategy. Uh

so we just for for the doctor's

perspective, it

really doesn't matter. So we're we're

doing our job no matter what. If the

patient uh

engages with his own disease uh then

we're happy to help and happy to

uh talk about the disease and give all

the relevant information. And we also

have patients

who are doing the exact opposite and

just

saying do whatever is necessary. Um

just just treat me. I don't want to I

don't want to look at the MRI. I just

want you to do your thing basically. Uh

I think it's

it's different for every patient and you

have to find your own strategy for

yourself to get get along with this

disease that you have and that you're

being treated for and there's no right

or wrong way.

And uh certainly it for uh some

individuals to get as much information

as you can about your own disease

uh is helpful and for others it can be

not helpful too. So it's very very

different. What I what I want to know is

uh because you know, you're both

scientists at the end of the day is what

delivers the better outcomes? I'll do

whatever it takes. If like ga- engaging

with the disease delivers better

outcomes, I'll do that. If not engaging

with the disease delivers better

outcomes, I'll do that. I'll do whatever

it takes to to ensure the best outcome

if you like, you know. But I guess

there's no scientific data on that yet.

I'm not aware of such data, but there's

a there's an own field, you know,

facing that that's called

psycho-oncology.

It's how you deal with a disease

um and you um we have a service where we

uh where we treat patients um by

specialists on psycho-oncology and that

that

uh we know that mood plays a role. We

know that sports plays a role and uh so

many different uh uh other things we

call supportive medicine around cancer

um

and that is important, but I think it's

a philosophical question you're raising.

Uh I think everyone everyone has to

find his or her own way and uh but at at

the end of the day, I think best case

scenario is that you are that you're

guided

by your doctor, right? And and maybe

also oh

throughout the path your your your views

will be changing.

And you will enter the cave or you will

leave the cave or escape, whatever. I

mean

um that's a that's a really

philosophical question here.

I know that every time I do sport I I

just like I I I specifically for this

podcast didn't want to make it a

consultation with a doctor, but um

so um

I find it interesting that during this

period however I feel, whether I have a

one headache or a two headache whatever

the level is, when I do sport it doesn't

get worse.

And when I just do sport it always feels

better to me. Always always at the end

of the day. So I find movement is very

important. I'm going to give uh

Professor Pepper and then uh you uh

Professor Mutter the last your final

word before I say thank you and goodbye.

It's been a wonderful time. I really

appreciate you spending the time with me

and whatever audience we managed to

gather to get together. Dr. Pepper,

final words or anything that you missed.

Yes. Uh so um I wanted to return the

thank you for you for first of all for

you uh participating in our trial um

first and foremost. So uh this is

something that we as researchers are

always always always very grateful for

because um if you if you go to

conferences

um you and you see people presenting

their work uh something that's written

on all the on all the slides at the end

uh when it comes to uh thanking thanking

people and thanking collaborators um it

mostly always says we also we we thank

our patients and their families for

participating in the trial. And when you

first start in this um in this cosmos of

uh

of medicine, you maybe think it's a

little bit of a

little bit weird or that it's something

that's expected, but if you really

engage in clinical trials, you

really understand that is something that

you are for as a as a doctor as a

treating physician, you are grateful for

the patients who are put their faith in

you and

um

that you try to do your job and um

giving them your time and your your

health for for that matter uh just to um

to get

well themselves, but also help you to

try to change something and develop

something that's been beneficial. So

very very

uh

much uh thank you on that regarding

that. And also very much thank you for

uh the possibility to speak about the

trial and the treatment and uh the

perspectives here in Germany.

I'll I'll yeah, so thank thank you. I'll

I'll have something to say about that,

but I'll I'll get I'll get Dr. Mutter to

go next and then I'll finish up with

something that you'll enjoy.

Yeah, right. I I would like to take the

chance of closing the loop by saying um

um um please invest into, you know,

medical companies and this this is what

keeps the system rolling.

It's very important for us to work with

especially in the in the surgical field

to work with medicinal product companies

try to invent new um new devices that we

use to improve uh surgery, improve

outcomes at the end.

Um and not everything [clears throat]

can be done by public funding and um and

it is of course in the interest of of of

all those companies to bring their

product onto the market and they need an

investors and um this is how how this

all works and um and I just want to take

the chance of I know it's a risky

business. Um

I I couldn't I couldn't tell cuz cuz I I

don't invest. But um

I know that that and we are working

together with companies that really rely

on this and and and trials that couldn't

be done without that and that's the

reason why I I just want to say these

words.

And I just want to add that if

if any So I'm not a I might become an

invent investor in a small way in

companies that may save my life who

knows but if you like you can probably

find that your way to them directly but

I would strongly encourage

the two of you to be involved in the

investing side as well even

if I found the companies

or or take some technology that you have

that you can get patented and so we can

talk about that sometime in the future.

You should know that I pride myself or I

one of the questions that I asked Dr.

Pepper at the end of the day I just

wanted to know that I was a good patient

and that I was

liked by the staff and I'm I'm a certain

personality so I was not to say

difficult but I once there was a huddle

there was a Wednesday morning huddle of

the of the group that

go rounds together and and I was like

totally out of line like rushing to the

hospital to one of the doctors there's

one person that

Dr. Mitra I don't know if you know about

but so I was so scared because he's a

male nurse an older male nurse

and I thought no he's not going to be

he's not going to be good for doing a

blood sample for me I'd rather have a

young kind of cute looking nurse and it

turned out that he was the best nurse

ever he he finds the most difficult

veins and he even has a name it's okay

if I mention his first name that's okay

isn't it?

So so his name is Mustafa and he he's

known around the hospital anyway so it's

it's a privilege for me to have met you

I would just say as well that

I really am blown away by um

how dedicated

the two of you are and other people are

to healing patients and advancing

science.

And I think that in a different world

we'd have less less hedge fund managers

and finance people and more people like

you we would make a better world and

maybe this will contribute to that so

thank you so much I look forward to

seeing you

as a as a patient at some point but I

hope that that all goes well and you

never have to treat me ever again you

know so um

who knows we'll see. Thank you so much.

It's crossed.

>> Thank you.